Abstract
Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.
Highlights
Pathological left ventricular hypertrophy (LVH) is the most powerful independent predictor for cardiovascular mortality (Levy et al, 1990; Mudd and Kass, 2008)
Consistent with 14 days of transverse aortic constriction (TAC) resulting in a compensated LVH model, body weight (BW) and lung weight (LW) (Table 1) remained unchanged in TAC mice compared to shamoperated mice
We examined the molecular signalling pathways mediating LVH in both WT and Trpm4 cKO hearts after 2 days of TAC, a time at which molecular signalling is already activated in response to the increased haemodynamic load induced by TAC (Yu et al, 2021), but before measurable LVH has developed
Summary
Pathological left ventricular hypertrophy (LVH) is the most powerful independent predictor for cardiovascular mortality (Levy et al, 1990; Mudd and Kass, 2008). Our previous experimental work has demonstrated that Gq-coupled receptors and the calcineurin-NFAT pathway are essential for the induction of LVH in response to angiotensin II, neither are required for the induction of LVH in response to transverse aortic constriction (TAC), the most common experimental model of LV pressure overload (Yu et al, 2021), and one not associated with activation of the renin–angiotensin system (Zou et al, 2004). We demonstrate that loss of cardiomyocyte TRPM4 significantly attenuates the development of LVH observed in response to TAC in WT mice This effect is associated with reduced activation of the CaMKII-HDAC4-MEF2 pathway
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